Project Summary Three of the five top-selling drugs contain fluorine. In 2013, 9 of 27 new small molecules approved by the FDA for therapeutic use contained fluorine. Currently, due to a lack of synthetic methods, inclusion of multiply fluorinated aryl groups on the central core of a drug scaffold is rare. Ongoing, selective mono-fluorination methods cannot address this issue. A conceptually attractive alternative is to utilize commercially available perfluoroarenes and selectively reduce or substitute the undesired fluorines. The goal of this proposal is to develop synthetic methods that will allow the perfluoroarenes to serve as linchpins for the synthesis of multiply fluorinated drug scaffolds. To realize this goal we will activate the robust perfluoroarenes with an electron (Specific Aim 1) and via nucleophilic addition (Specific Aim 2). We will show that perfluoroarenes can undergo a number of C?C forming reactions that take place via C?F functionalization. We will also show that perfluoroarenes are also quite susceptible to nucleophilic addition by developing a number of substitution reactions that lead to biologically relevant motifs. Finally, we will develop novel catalysts (Specific Aim 3) that expand C-F functionalization strategies. The three aims are complimentary, and synergistically approach the aforementioned problem. Upon completion of these goals, it is expected that medicinal chemists will be able to access and utilize polyfluorinated arenes with far greater ease and diversity than currently possible. This will positively influence the design of new pharmaceuticals by significantly expanding access to multiply-fluorinated arenes and significantly reducing the time needed to synthesize such molecules and, consequently, the time needed to discover new drugs.